In this application for an NIMH Mentored Patient-Oriented Research Career Development Award (K-23), the candidate proposes to develop expertise in the study of major depressive disorder (MDD), clinical evaluation of treatment response, and brain energy metabolism. The research component of this proposal involves an open, acute and prospective follow-up of subjects with MDD treated with citalopram. Several studies utilizing phosphorus-31 magnetic resonance spectroscopy (P31-MRS) have shown that subjects with MDD, compared with healthy volunteers, appear to have decreased brain levels of several compounds characteristic for the cellular high-energy phosphorus metabolism. However, no studies to date report measurements before and after treatment. We propose to study MDD subjects who respond to antidepressant treatment, MDD subjects refractory to antidepressant treatment, and healthy volunteers. We will use P-31 MRS to measure brain levels of phosphorus compounds at baseline, two weeks into treatment and at the end of treatment (in order to separate the brain metabolic effects of antidepressant medications from the effects of MDD). We aim to correlate brain levels of high-energy phosphorus compounds with the clinical symptoms of MDD and the clinical response to antidepressant treatment. The study outlined here has the potential to advance our knowledge on the pathophysiology of MDD. With the K-23 Award, the candidate seeks to gain expertise in: (1) designing and carrying out clinical trials for MDD, (2) biostatistical methods, and (3) magnetic resonance spectroscopy techniques as applied to clinical trials. The career development plan in this proposal includes a rich, multidisciplinary didactic component, with coursework in research design and biostatistics at the Harvard School of Public Health, magnetic resonance imaging at the Massachusetts Institute of Technology, and research ethics. The integrated research study and career development plan outlined here will lay the foundations for future independent investigation by the candidate in this area. The development of a larger scale R01 project investigating the role of brain energy metabolism in a population of treatment-resistant subjects with MDD will be started during the last two years of the award period.